Elucidating the genetic pathways regulating growth remains a fundamental challenge facing medical science. The essential genetics of normal human growth is not well understood; moreover, human growth problems are a ubiquitous feature of medical pathophysiology. The overall goal of this application is to better understand the genetic pathways controlling growth. Specifically, growth of the zebrafish fins will be used to test the hypothesis that blood vessels and endothelial cells play a critical role in regulating growth. Zebrafish fins grow by alternating cycles of saltation and stasis. long fin, a fin overgrowth mutant, bypasses the stasis phase of the fin ray growth cycle. Interestingly, the fin overgrowth phenotype in long fin is autonomous to the fin ray endothelium. In one set of experiments, custom microarrays will be used to profile gene expression in the fin ray endothelium of long fin mutants and wild-type zebrafish. This gene expression aim will reveal novel genes and pathways operating in the endothelium that are critically important in regulating growth of the surrounding tissue. In another set of experiments, the role of the endothelium vis-a-vis growth control will be explored in two additional fin overgrowth mutants, primrose and rapunzel. Finally, the fin overgrowth mutant primrose will be mapped and cloned. Compelling data suggest that primrose fin overgrowth phenotype may result from a lesion in the endothelin-signaling pathway, a pathway known to be important in endothelial cell biology. The candidate is a clinician-scientist, board certified in pediatrics and pediatric critical care medicine. He initiated work on growth in the zebrafish fin with support from the Child Health Research Center Pediatric Scientist Development Award, and intends to pursue this new line of investigation regarding the role of blood vessels in growth control with support from this application. Knowledge gained from this application will provide sufficient preliminary data for independent funding subsequently. This research will be initiated in the laboratory of Dr. Stephen Johnson in the Department of Genetics at Washington University School of Medicine. The mentor is a world leader in both experimental zebrafish biology and zebrafish genetics and genomics. The proposed research will provide important training in microarray analysis, experimental embryology, and in mapping and cloning zebrafish mutations, training that will prove crucial for the candidate as he transitions into an independent clinician-scientist.